Multiple myeloma (MM) is a B-cell malignancy characterised by the accumulation of terminally differentiated B-cells (plasma cells) in the bone marrow. Recent research has identified some of the genetic and molecular defects that occur in myelomatous plasma cells (Drach, J. et al. (2000) Cancer Res Clin Oncol. 126:441; Ludwig, H. et al. (1999) Annals Oncol. 10 (6):S31). These data indicate that multiple molecular events result in profound genetic instability of the cells, resistance to chemotherapy and increased bone marrow neovascularisation. The current therapy for MM is high dose chemotherapy and/or autologous peripheral blood stem cell transplantation. At present, the latter treatment is favoured due to a higher 5 year survival rate (52% versus 12%). Recently, antiangiogenic agents such as Thalidomide have produced an objective response in approximately 30% of refractory patients. MM is irreversibly fatal despite these drastic therapies, with median survival times of 4-6 years depending on mode of treatment (Kyle, R A. et al. (2001) The Oncologist. 6 (2):119).
There are currently 40,000 patients with MM in the United States, with an estimate that approximately 14,000 new patients are diagnosed each year (Chauhan, D. and Anderson K C. (2001) Apoptosis. 6 (1-2): 47). The incidence of MM worldwide is between 1.5-4.5/100,000/year depending on the country (Hurez, D. (1993) Revue du Praticien. 43(3):271).
The malignant B-cells in MM produce excess amounts of light chain, a component of immunoglobulin, and these light chains are present in the serum and urine of individuals with this disease. Approximately 70% of MM patients produce light chains of kappa-type, with the remaining 30% being lambda-type (Kyle, R A. (1999) Path Biol. 47(2):148).
K121 is a murine monoclonal antibody (mAb) that specifically recognises human free kappa light chains and an antigen expressed on the surface of kappa-type myeloma cells. This antigen is designated kappa myeloma antigen or KMA (Boux, H A. et al. (1983) J Exp Med. 158:1769). It has been established that KMA consists of free kappa light chains expressed in non-covalent association with actin on the cell membrane (Goodnow et al. (1985) J. Immunol. 135:1276). K121 does not exhibit cross-reactivity with any normal or malignant lymphoid cells or with intact human immunoglobulin molecules (Boux, H A et al. (1984) Eur. J. Immunol. 14: 216).
A quantitative immunoassay for measuring free kappa light chains in the serum and urine of patients suffering from MM has been developed using K121 (Axiak, S M. (1987) J Immunol Methods. 99:141). The recent literature suggests that quantification of free light chains may be used to monitor the progress and response to therapy of these patients (Drayson, M. (2001) Blood 97 (9):2900).
It has also been suggested that K121 may be used to deliver cytotoxins to kappa myeloma cells (Goodnow et al. (1985) J. Immunol. 135:1276). Indeed, an immunotoxin comprising the cytolytic peptide melittin linked to a K121 scFV fragment (scFv-mel) has been developed as a potential therapeutic agent for the treatment of MM (Dunn, R D. et al., (1996) Immunotechnology 2: 229).